A characteristic feature of the menopause is a marked attenuation in the production and release of ovarian steroids, such as estradiol and progesterone. However, the impact of these changes on human physiology, especially within the central nervous system (CNS), is far from being clear. We have already shown that female rhesus macaques, like women, undergo menopause, and that a change in plasma FSH and inhibin B levels represents the first endocrine manifestation of this event. We have also shown that plasma levels of the adrenal steroid, dehydroepiandrosterone (DHEA), fall markedly around this time. DHEA is one of the most abundant steroids in the circulation;it is released into the circulation in a circadian manner and is readily converted to estradiol in many tissues. The overall aim of the parent R01 grant (AG-029612) is to examine the interacting impact of adrenal and ovarian aging on the CNS of primates. Using the female rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that the aging-related attenuation of DHEA release exacerbates the perimenopausal decline in estradiol, and thereby negatively impacts central physiological processes such as cognition, learning, and attention, and leads to perturbation of the circadian sleep-wake cycle. Specific Aim 1 will use a battery of behavioral tests to assess differences between young adults, and old regularly-cycling and irregularly-cycling adults;the old animals will be tested both as untreated controls and also after extended treatment with "young" physiological levels of DHEA. Cognitive and behavioral assessments will include: 1) delayed response test of spatial working memory, which is particularly sensitive to aging and prefrontal cortex dysfunction;2) delayed non-matching-to-sample, a task probing primarily hippocampus-based memory;3) a visuospatial cueing test of visual attention that is estrogen-sensitive;and 4) a test of behavioral reactivity sensitive to amygdala damage. In addition, sleep-wake cycles will be continuously monitored using Actiwatch recorders, and MRI will be performed before and after DHEA replacement to monitor morphological and biochemical changes in the key brain regions. Specific Aim 2 will use a series of biochemical and histochemical methodologies to elucidate the plasticity that occurs within the CNS during adrenal-ovarian aging. Gene microarrays and RT-PCR will be used to identify genes that are differentially expressed in the CNS between young and old animals, regular and irregular old cyclers, and DHEA-treated and untreated old animals. The focus will be on genes encoding enzymes involved in the conversion of DHEA to estradiol, steroid receptors, and genes associated with key neurotransmitters systems and circadian clocks. Immunohistochemistry, in situ hybridization histochemistry, RIA and biochemical enzymology will be used to corroborate the results. Aim of Supplement: At the end of 2008, our pilot R21 grant (AG-026472) will be releasing 20 ovariectomized rhesus macaques, which have already been cognitively tested using the same procedures described in Specific Aim 1. More importantly, some of these animals have been (and still are) continuously exposed to hormone replacement therapy (HRT), involving combinations of estradiol and progesterone. We thus have a unique opportunity to integrate these additional animals into the parent DHEA-replacement study, with very little additional expense. This integration of old ovariectomized, estradiol-treated and estradiol/progesterone-treated animals represents a major strengthening of the original experimental design, because it will enable us to compare and contrast the efficacy of DHEA replacement therapy to that of more conventional HRT. PUBLIC HEALTH RELEVANCE: A characteristic feature of the menopause is a marked attenuation in the production and release of ovarian steroids, such as estradiol and progesterone. However, plasma levels of the adrenal steroid, dehydroepiandrosterone (DHEA), also fall markedly around this time. DHEA is one of the most abundant steroids in the circulation;it is released into the circulation in a circadian manner and is readily converted to estradiol in many tissues. The overall aim this research is to examine the interacting impact of adrenal and ovarian aging on the central nervous system of primates. Using the female rhesus macaque as a pragmatic animal model, we propose to test the hypothesis that the aging-related attenuation of DHEA release exacerbates the perimenopausal decline in estradiol, and thereby negatively impacts central physiological processes such as cognition, learning, and attention, and leads to perturbation of the circadian sleep-wake cycle.